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Journal of Antimicrobial Chemotherapy (2002) 50, 365-374
© 2002 The British Society for Antimicrobial Chemotherapy

Pharmacokinetic and antiretroviral activity in mice of oral [P1,P2-bis[2-(adenin-9-yl)ethoxymethyl]phosphonate], a prodrug of 9-(2-phosphonylmethoxyethyl)adenine

Luigia Rossi1, Sabrina Dominici1, Sonja Serafini1, Anna Casabianca1, Aurora Cerasi1, Laura Chiarantini1, Angela Gabriela Celeste2, Loredana Cappellacci3, Palmarisa Franchetti3, Mario Grifantini3 and Mauro Magnani1,*

1 Institute of Biochemistry ‘G. Fornaini’ and 2 Institute of Hygiene, University of Urbino, 61029 Urbino; 3 Department of Chemical Sciences, University of Camerino, 62032 Camerino, Italy

Received 19 December 2001; returned 26 March 2002; revised 7 May 2002; accepted 24 May 2002

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is an antiviral drug with activity against herpes viruses, Epstein–Barr virus and retroviruses, including the human immunodeficiency virus. Unfortunately, oral PMEA administration, as required for long-term therapy, is hindered by its low bioavailability. In the present study, the synthesis, oral bioavailability and antiretroviral activity of a new prodrug of PMEA, consisting of two molecules of PMEA bound together by a P-O-P bond (Bis-PMEA), are reported. Pharmacokinetic experiments in mice showed that the oral bioavailabilities of PMEA following oral gavage of Bis-PMEA or PMEA (at a dose equivalent to 28 mg of PMEA/kg) were 50.8 and 13.5%, respectively. These results correlate with the antiviral efficacy of Bis-PMEA administered orally at a dose equivalent to 50 mg/kg of PMEA in C57 BL/6 mice infected with the retroviral complex LP-BM5. Oral treatment with Bis-PMEA proved to be more effective than oral treatment with PMEA given at equimolar doses. Moreover, oral Bis-PMEA was more effective than intraperitoneal PMEA (50 mg/kg) in reducing lymphoadenopathy, hypergammaglobulinaemia and lymph node proviral DNA content, overall in the first weeks post virus inoculation. Bis-PMEA thus appears to be an efficient oral prodrug of PMEA without significant toxicity, at least in this mouse model.

* Corresponding author. Tel: +39-722-305211; Fax +39-722-320188; E-mail: magnani{at}uniurb.it


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